The objective of this proposal is to define behavioral consequences and cellular correlates of repeated drug exposure on alterations in incentive motivational processes and inhibitory control contributing to cognitive deficits in addiction. Neurobehavioral studies in humans and animals are beginning to define drug-induced alterations in cognitive-motivational processes, and brain imaging studies show altered cortico-limbic-striatal activity in drug abusers. Our studies in animals have contributed to the idea that drug-induced alterations in dopamine (DA) neurotransmission and protein kinase A (PKA) signaling may result in molecular neuroadaptations. Studies from the previous funding period are among the first to show that repeated exposure to PCP, cocaine or THC produces long-lasting cognitive impairments associated with inhibitory control in monkeys and rats, deficits characteristic of, and correlated with, DA dysfunction in regions of the frontal cortex. These cognitive impairments are concomitant with alterations in incentive motivational processes and enhanced subcortical DA function. Our new data show that these persistent drug-induced behavioral changes are also associated with, and can be mimicked by, increases in DA/PKA activity, suggesting that adaptations in DA-regulated intracellular signaling molecules may underlie alterations in motivational processes. Drug-induced increases in synaptic DA stimulate D1 receptors, which increase cAMP levels, leading to activation of PKA. PKA activation increases expression of transcription factors and phosphorylation of substrate proteins involved in neuronal excitability/plasticity such as the DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). The current research proposes an intensive examination of how repeated drug exposure persistently alters cognitive/inhibitory function, incentive motivation and DA/PKA signaling. In Aim 1, the effects of repeated cocaine, PCP, and THC on cognitive-inhibitory functions dependent on ventromedial vs. dorsolateral frontal cortex in monkeys and rats will be examined. In Aim 2, we will investigate the effects of drug exposure on incentive motivation using stimulus-reward learning and conditioned reinforcement, and expand these studies to monkeys and cocaine self-administering rats. An additional goal is to determine whether these drug-induced behavioral changes are associated with alterations in DA/PKA-regulated signaling pathways in cortico-limbic-striatal regions and correlate putative molecular changes with behavior. We propose to focus on the DA/PKA-regulated protein DARPP-32 because it can be used to assess both inhibition and amplification of DA/PKA signaling, and it is expressed in cortical-limbic as well as striatal regions. Aim 3 will directly test the hypothesis that reduced cortical PKA activity and enhanced limbic-striatal PKA activity can mimic the effects of prior drug exposure using local infusions of PKA inhibitors/activators and examine if drug-induced deficits can be reversed by infusions of PKA modulators.